Studies on tissue-speciflc pathogenicity of picoronaviruses

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Piconraviridae is a large family of positive-stranded RNA viruses. The pathogeniciy of each virus in this family is quite different. For example, poliovirus, coxsakievirus, hapatitis A virus, rhinovirus cause acute encephalitis, myocarditis, hepatitis and common cold, respectvely. Aim of our research is to elucidate molecular mechanism to determine tissue-specific pathogenicity of pjcoraaviruses.1.Production of transgenic mice expressing human poliovirus receptor (PVR) gene. PVR has been considered as a major determinant of host range restriction and tissue tropism. To determine the influence of PVR expression on the tissue tropism, we have produced two transgenic mice in which PVR is expressed with a different distribution pattern. In one model, hg-PVR mouse, PVR gene is expressed with its own promoter and PVRis distributed only in neurons but not glial cells. In the other, CAG-PVR mouse, PVRis expressed ubiquitously. After intracerebral inoculation of poliovirus, the former showed a paralytic disease that resembles human poliomyelitis and died, while the latter survived without paralysis. The results suggested importance of PVR expression patterns on neuropathogenesis of poliovirus.2.Pathogenicity of chmeric viruses. We produced chimeric viruses between poliovirus and CVB3 virus. A poliovirus chimera having 5'-noncoding region of CVB3 showed neuropathogenic property similar to poliovirus. A CVB3 chimera having 5'-noncoding region of poliovirus did not show neuropathogenic property. The results suggested the importance of coding region of each virus for the tissue-specific infection.3.Construction of Infectious cDNA for enteorhlrus (EV)71. EV71 is also a neurotropic virus, which is not analysed extensively. We have constructed an infectious cDNA clone for an EV71 strain, SK006/Malaysia, which was isolated from a rectal swab of a patient died of fatal encephalitis. This cDNAclone will be a powerful tool to investigate neurotropism of EV71.